Salts of ergotocin and process of producing them



Patented Nov. 5, 1940 PATENT OFFICE SALTS or ERGOTOOIN AND rnocnss F PRODUCING THEM Morris S. Kharasch, Chicago, 11]., and Romeo Ralph. Legault, Lewisburg, Pa., assignors to Eli Lilly and Company,.Indianapolis, Ind., a corporation of Indiana No Drawing. Application July 24, 1936, Serial No. 92,462

3 Claims. (01. 260-236) Our invention relates to salts of ergotocin, a hitherto unknown active principle of ergot, and to the process of obtaining such salts.

Our present application is a continuation in part of our co-pending application Serial No. 20,628, filed May 9, 1935, now Patent No. 2,156,242, granted April 25, 1939, for an ergot derivative and process of obtaining it.

The new active principle of ergot which we 1 call ergotocin is also known by the names of ergometrine, ergostetrine, ergobasin, and ergonovine. 1008, 1012, and 1013.) For convenience, however,

, regardless of what may eventually become ac- 5 cepted as the name of such new active principle, we shall refer to it by the name ergotocin, Which is the name by which we denote it in our aboveidentified patent application and patent.

Ergotocin in the form of a free base does not 2' keep well, but turns brown in the air within a week or two. For that reason, and for other reasons, it is desirable to have ergotocin in the form of a salt; for the salts of ergotocin have excellent keeping qualities.

5 However, not all acids combine with ergotocin to yield salts which are readily obtainable in welldefined crystalline form. For instance, we find that many of the monocarboxylic acids tested by us, such as acetic acid, monochloracetic acid, pro- 3 pionic acid, butyric acid, lactic acid, benzoic acid,

monochlorobenzoic acid, 2,4-dichlorobenzoic acid,

paranitrobenzoic acid, phenyl-sulfonic acid, and others, do not give crystalline salts of ergotocin which can be readily isolated by'the process we are about to describe. On the other hand, we find that dicarboxylic acids, particularly those of the aliphatic series, and most particularly those which contain not more than five carbon atoms, give by that process crystalline salts of ergotocin which 40 are quite stable and which can readily be crystallized from solvents. It is these dicarboxylic acids, indeed, which make the isolation of ergotocin a relative simple procedure, in addition to making it possible to obtain ergotocin in a crystalline 45 form with good keeping qualities.

Among the most important dicarboxylic-acid salts of ergotocin are probably the maleate, fumerate, succinate, tartrate, oxalate, malonate, and malate; and they are the ones to which our 50 more specific claims are directed.

Among the dicarboxylic acids, we find that those in which the primary ionization constant of the acid is somewhere between l0- to are the best suited for this purpose.

55 There is even a rough relation between the (Journal A. M, A., March 21, 1936, pages primary ionization constant of the acid and its suitability for this purpose.

Maleic acid has a primary ionization constant of 1.5 10 and is an excellent acid for our purpose. Oxalic acid has a primary ionization 5 constant of 3.8 10- and is also quite useful for our purpose. Maloni-c acid, which has ,a primary ionization constant of 1.6 l0 and malic acid,- which has a primary ionization constant of 4x 10- are not so good as maleic and oxalic 10 acids, but still satisfactory; while ,succinic acid, which has a primary ionization constant of 6.6x 10 is not particularly suitable for our purpose, although it is still better than any monocarboxylic acid of which we are aware.

We may prepare these ergotocin salts of suchdicarboxylic acids from a dry chloroform solution of ergotocin, as follows:

To such a dry chloroform solution of ergotocin, or to a solution of ergotocin in other appropriate '20 solvent of the chana'cter indicated, there is added an ether solution of the desired acid; for instance maleic acid or oxalic acid. The ergotocin salts of these dicarboxylic acids are insoluble in'et-her and in chloroform and mixtures thereof, so that the ergotocin salts of such acids usually separate at once. In some cases" it is best, for complete precipitation, to add a fairly large volume of ether. For instance, if the base ergotocin is contained in ethyl alcohol or 0 butyl alcohol, the procedure just outlined may be followed, but the precipitation of the ergotocin salt is facilitated by several volumes of ether.

The ergotocin salts of dicarboxylic acids which are thus obtained from chloroform or other solu- 5 tion by the addition thereto of an ether solution of the dicarboxylic acid, are suitably separated from the supernatant liquid, as by filtration. Suchsalts may be purified by recrystallization from suitable solvents, such for instance as ethyl 40 alcohol, butyl alcohol, etc.

The following example indicates the procedure in connection with the preparation of ergotocin maleate.

To a chloroform extract of ergotocin obtained from 500 pounds of defatted ergot in about 8 gallons of chloroform is added an equal volume of ether containing 10 grams of maleic acid. This causes a precipitate of ergotocin maleate; which is separated from the supernatant fluid, as by filtration. We obtain yields of ergotocin maleate from that amount of ergot of about 13.5 g.

The ergotocin maleate thus obtained-may be purified by recrystallization from ethyl alcohol if desired.

Other dicarboxylic acids may be used instead of maleic acid, in generally corresponding amounts, to give ergotocin salts corresponding to those acids.

The ergotocin salts of the dicarboxylic acids are well-defined crystalline substances, but apparently have no definite melting point. Upon heating they turn black, and melt somewhat at a temperature varying from 165 C. to 178 C., and then merely decompose with the evolution of a gas, as indicated by puffing up of the material in a melting-point tube, but they do not completely melt even though the temperature is raised to the neighborhood of 190 C.

These ergotocin salts of the dicarboxylic acids are all onium salts of quinquevalent nitrogen. They are freely soluble in water, and the solutions are colorless; but with an exceedingly pale blue fluorescence, particularly noticeable at the meniscus, when in higher concentration, as of the order of 0.5 mg. per cc. or greater. These salts are highly suitable for obtaining ergotocin in pure form, for they can be crystallized very readily from ethyl alcohol or butyl alcohol. The addition of an alkali to a solution of the ergotocin salt, followed by extraction with chloroform, enables one to obtain the free base in very pure condition.

In addition to the organic salts of ergotocin, of the dicarboxylic acids, we may obtain also an ergotocin salt of an inorganic acid. For instance, we may obtain ergotocin phosphate, by adding an ether solution of phosphoric acid to the chloroform or other solution of the base ergotocin. This ergotocin phosphate is very freely soluble in water, but it is not as definitely crystalline as the organic salts but tends to be amorphous. It has no definite melting point, but decomposes upon heating.

When any of the salts of the known ergot alkaloids (ergotoxine, ergotinine, ergotamine, ergotaminine, ergoclavin, and sensibamine) are heated for from three to four minutes with sodium hydroxide, one molecule of ammonia is split ofi" quantitatively. In contrast, when the salts of ergotocin are similarly heated with sodium hydroxide, there is at most only a faint trace of ammonia, and sometimes not even that.

When the salts of ergotocin are administered orally to human mothers they induce strong uterine contractions. The efiective oral dose of any of the ergotocin salts mentioned, for the human mother, is from 0.3 to 0.5 mg. When orally administered in such doses the uterine contractions usually start within from 4 to 8 minutes after such administration. The uterine motility which is initiated persists for from 2 to 4 hours. It is characterized by marked and persistent uterine tone, and frequent uterine contractions. During the first 15 to 20 minutes of its action there is marked tetany.

This is in strong contradistinction to the effects of even the so-called active members of the known ergot alkaloids or of their salts. The alkaloids ergotoxine, ergotamine, and sensibamine, and their salts, are uniformly ineffective when administered orally to human mothers in doses of 2.0 mg. Even in larger doses, of 3.0 or 4.0 mg., they do not uniformly induce uterine activity. In still larger oral doses, of from 6.0 to 9.0 mg., the so-called active members of the known ergot alkaloids and their salts do produce uterine activity; but such doses, and even doses of 3.0 or 4.0 mg. are dangerous, because of their toxic effects on the patient.

The salts of ergotocin are also efiective when administered parenterally-subcutaneously, intramuscularly, or intravenously. The efiect on intravenous administration is particularly striking. The effective dose for intravenous administration is 0.1 to 0.2 mg; and powerful uterine contractions are usually produced within less than a minute, usually from 10 to 20 seconds, following the injection.

An outstanding feature of the salts of ergotocin on intravenous injection is that the material does not cause any toxic symptoms, any change in the blood pressure, any nausea or cyanosis, any gastrointestinal upsets, or any of the other grave symptoms that have been recorded in the literature following the intravenous injection of ergotamine tartrate or ergotoxine ethanesulfonate. Ergotocin in that respect is a unique pharmacological principle, in that it seems to act specifically on the uterine muscles. The toxicity of ergotocin and its salts to mice and rats is of the order of 250 mg. per kg. of body weight.

We claim as our invention:

1. Substantially pure ergotocin maleate.

2. Substantially pure ergotocin succinate.

3. A salt of substantially pure ergotocin and an acid of the class consisting of maleic acid and succinic acid.

MORRIS S. KHARASCH. ROMEO RALPH LEGAULT. 

